systemic embolic events (see) in atrial fibrillation...

DOI: 10.1161/CIRCULATIONAHA.115.018172

1

Systemic Embolic Events (SEE) in Atrial Fibrillation:

SEEing Embolic Risk More Clearly

Running title: Chatterjee et al.; Systemic embolism in atrial fibrillation

Neal A. Chatterjee, MD1; Steven A. Lubitz, MD, MPH1,2

1Cardiology Division; 2Cardiac Arrhythmia Service, Massachusetts General Hospital,

Harvard Medical School, Boston, MA

Address for Correspondence:

Steven A. Lubitz, MD, MPH

Cardiac Arrhythmia Service

Massachusetts General Hospital

55 Fruit Street, GRB 109

Boston, MA 02114

Tel: 617-643-4017

Fax: 617-726-3852

E-mail: [email protected]

Journal Subject Codes: Anticoagulants:[184] Coumarins, Anticoagulants:[185] Other anticoagulants, Stroke:[53] Embolic stroke, Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Etiology:[8] Epidemiology

Key words: atrial fibrillation, atrial flutter, arrhythmia, Editorial, arrhythmia, embolism, fibrillation, flutter

1Cardiology Division; 2Cardiac Arrhythmia Service, Massachusetts General l HoHoHospppitititalalal,

Harvard Medical School, Boston, MA

AAdA dddress for CoC rrrresppoonndennnceee:

Stevvvenenen AAA. LuLuL biiitztztz, MDMDMD, MMMPH

Cardiac Arrhythmia Service

by guest on June 14, 2018http://circ.ahajournals.org/

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Thromboembolism is central to atrial fibrillation (AF) related morbidity.1 The pathogenesis of

intra-cardiac thrombus formation in AF is linked to each component of Virchow’s triad including

atrial stasis, endothelial dysfunction, and a systemic hypercoagulable state.2 Although embolism

of cardiac thrombi can involve any vascular territory, there has been a historical focus on

cerebral embolism, an outcome associated with substantial disability and mortality.3 In contrast

to the well-characterized risk and sequelae of cerebral embolism, much less is known regarding

the clinical risk factors and outcomes associated with systemic embolic events (SEEs) in AF.1, 4-6

In this issue of Circulation, Bekwelem and colleagues improve our understanding of the

epidemiology and prognostic implications of systemic embolism in AF.7 They retrospectively

pooled data from four published randomized trials of anti-platelet or anticoagulant therapy in AF

patients encompassing a total of 37,973 individuals (Table 1).8-11 The investigators re-

adjudicated suspected SEEs using a harmonized classification scheme. An SEE was defined by

both clinical and objective evidence of sudden loss of end-organ perfusion. They then examined

the risks of both 30-day and long-term morbidity in relation to SEEs.

Overall, 221 SEEs occurred in 219 individuals during a mean follow-up of 2.4 years. The

incidence of SEEs (0.24/100 person-years) was lower than cerebral embolism (1.92/100 person-

years) and comprised 12% of clinically-recognized thromboembolic events. Anatomically, about

60% of SEEs involved the lower extremities, whereas about 30% occurred in the visceral-

mesenteric system, and only 11% occurred in the upper extremities. Most patients underwent an

invasive procedure as part of their clinical management. SEEs were associated with similar and

significant 30-day mortality when compared to stroke alone (24% vs. 25%). SEEs were

associated with about a 4-fold increased risk of long-term mortality, as compared to a nearly 7-

fold increased risk of mortality associated with ischemic stroke.

pooled data from four published randomized trials of anti-platelet or anticoagulantntnt tttheheherararapypypy iiin n n AAFA

patients encompassing a total of 37,973 individuals (Table 1).8-11 The investigators re-

adjuudididicacacateteteddd susus spppececcted SEEs using a harmonized d d clclclaaassification scheme. AAAn SEE was defined by

bbobothhh clinical annndd d oobjejeectctc iviviveee evevevidididenenncecee of ff ssuddddddenenn losss of enenenddd-orororgagagan n pepepe frfrfusususioon. TTThehehey thththenene eeexaxaamimiminenened

hhhee e riririsks s of bbbotoo h 3000-dayayay andd llononong-gg tetetermrmrm mmmorbbbidddity innn reelalalatttionnn ttto SESEEEsEsEs...

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This study has a number of strengths that distinguish it from prior literature. Collation of

readily available, ethnically diverse patient cohorts yielded the largest reported assessment of

AF-related SEEs to date. Careful endpoint ascertainment and independent re-adjudication of

events with pre-specified diagnostic criteria enhance the validity of the results. Comprehensive

clinical descriptions of SEEs, including anatomic distribution and diagnostic methodology,

provide a detailed understanding of the different arterial beds commonly affected by peripheral

embolism in AF.

The findings of Bekwelem et al.7 should be interpreted in the context of the cohorts

included and study design. First, while the collated studies have similar baseline characteristics

(Table 1) there was significant heterogeneity in therapeutic exposure (anticoagulant vs. anti-

platelet) as well as relatively short follow-up time. Thus, the reported SEE rate represents a

‘blended’ rate among patients taking either anticoagulation or anti-platelet therapy and does not

reflect the long-term ‘natural history’ of AF. Second, given the relatively low incidence of SEEs,

the study was likely underpowered for several of the subgroup analyses presented, including age,

sex, and location of peripheral embolism. Third, the reliance on ‘clinically-evident’ end-organ

ischemia is practical though likely underestimates the ‘true’ incidence of systemic embolism,

particularly to abdominal visceral organs which have a rich network of collateral circulation

which may mitigate the ischemic insult of embolic phenomenon.1, 6 Fourth, some peripheral

embolic events could reflect lower baseline vascular reserve (eg. related to prior SEEs,

atherosclerotic burden, or anatomically smaller vessels) or more significant embolic burden. This

may explain the identification of prior SEEs and peripheral arterial disease as risk factors for

incident SEEs and may confound analyses of mortality.

Systemic Embolism in AF – Unique Events or Additional Embolic Destinations?

Table 1) there was significant heterogeneity in therapeutic exposure (anticoagulalaantntnt vvvs.s.s. aaantntnti-i-i-

platelet) as well as relatively short follow-up time. Thus, the reported SEE rate represents a

bleendndndededed’’ rararatetete amomomong patients taking either anticococoagagagulation or anti-platteleleletee therapy and does not

eeefllleect the longgg-t-t-terrm mm ‘‘n‘natataturururalalal hhhiiistststororory’y’y’ ooof f AFAFAF.. SSSecoondd, gigigivvvennn thththee rerr lalalatititivevevellyly lowww iiincncncidididenene cecece ooof f f SESESEEEEs,

hhhee e stststudu y wawaasss likkek llyl uundndnderpooowewewered d d foff r r r seeeveerrralll of thththe ssuubbgbgrorooupupup aanananalylyysess sss pprp esssenennted,,, innncluudiing aaggeg

eeex, aaandndnd lllocococatatatioioionnn ofofof ppperereripipipheheherararalll ememembobobolililismsmsm. ThThThiririrddd, thththeee rererelililiananancecece ooonnn ‘c‘c‘clililinininicacacalllllly-eveevidididenenent’t’t’ eeendndnd oo-orgrgrgananan


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Should an SEE be regarded as a distinct AF outcome or yet another embolic destination? Given

that the vast majority of patients with thromboembolism in this study experienced either stroke

or an SEE alone (~97% of embolic events), one might speculate that patients are uniquely

predisposed to either incident stroke or SEEs. The authors identify several clinical

characteristics more prevalent in patients with incident SEEs compared to stroke including

female gender and white ethnicity as well as a history of smoking, prior myocardial infarction,

previous SEEs, and peripheral arterial disease. Female gender and SEEs have been linked

previously4 and others have identified increasing age, severe left ventricular dysfunction and

echocardiographic evidence of left atrial appendage thrombi as additional risk factors for SEEs

compared to stroke in AF.12

The incidence and anatomic location associated with cardioembolism may also be related

to other factors. Anatomic distribution is generally influenced by the character of arterial

branching and the course of blood flow.1, 6 Increased thrombus size has been reported to favor

peripheral rather than cerebral embolic destination.12 Limited histochemical comparison of

central versus peripheral thrombi in AF is suggestive of differing biology with in situ thrombi

comprised primarily of amorphous debris and fibrin in contrast to embolic thrombi comprised of

fibrin and platelets.13 Regardless of whether patients are predisposed to specific embolic

destinations, the contribution by Bekwelem and colleagues underscores the substantial morbidity

associated with embolism of any kind.

Clinical and Therapeutic Implications of Identifying SEE Risk in AF

Given that several SEE risk factors (eg. female gender, peripheral vascular disease, prior

myocardial infarction) are included in stroke prediction algorithms it is unlikely that the report

by Bekwelem et al.7 will significantly modify the decision to initiate anticoagulation. Indeed, the

compared to stroke in AF.12

The incidence and anatomic location associated with cardioembolism may also be relatedd

o othththererer fffacacactototors. AnAnAnatomic distribution is generaallllllyyy ini fluenced by the chhhararracter of arterial

bbrbrannnching and d thththe cooouuursesese ooofff blblbloooood dd flflflowww.1, 11 66 IIIncncncreasseed thrhrhromomombububus sisisizeee hhhaaas ss bbeennn rrreepeporororteteted tototo fffavavavoroo

peeeririr phphpheral rratatathehh rr r thhhan ceere ebrrralala eeembbboloo iccc dddestitiinaaationn.1112 LLLimmmittededed hhhissstooochhhemmmiicalll cooompapaariririsonn ooof

cececentntntrararalll veeversrsrsussus ppperereripipipheheherararalll thththrororombmbmbiii ininin AAAFFF isisis sssugguggegegessstititiveeve ooofff dididifffffferererinininggg bibibiololologogogy wiiwiththth iniin sitititu ttthrhrhromomombibibi


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CHA2DS2-VASc score demonstrated similar discrimination and reclassification of clinical

outcomes when risk was defined either as stroke-alone or a composite of stroke and SEEs.14

Nevertheless, the study suggests that current efforts being considered for stroke prevention might

have extended value for SEE prevention. For example, given the morbidity attributable to SEEs,

should cardiac rhythm monitoring be implemented to identify subclinical AF in patients with

SEE risk factors such as peripheral arterial disease (Figure 1)?15, 16 Such initiatives may be cost-

effective for stroke prevention17 and are currently being evaluated.18-20 Similarly, would

enhanced cardiac rhythm monitoring to detect AF alter management in patients with visceral

embolism or peripheral ischemia without known AF, akin to efforts to identify a cause for

cryptogenic stroke?21 At what expense would AF prevention prove cost-effective altogether for

the reduction of embolic morbidity, if it were achievable? Practically, answering such questions

may be challenging owing to the relatively low event rates and large sample sizes necessary.

Therefore, at present it appears prudent to exercise increased vigilance for AF detection in

patients either at high-risk for systemic embolic events or with unexplained peripheral ischemia

that may be of embolic origin.

Bekwelem and colleagues have contributed significantly to our understanding of the

spectrum of thromboembolic risk in patients with AF. Their report provides us with estimates of

the incidence of SEEs, the arterial beds most commonly affected, and the morbidity associated

with such events. By opening our eyes, these data help us “SEE” embolic risk more clearly.

Ultimately such clarity will guide more effective application of therapies to stem the rising tide

of AF22 and thromboembolic morbidity.

Conflict of Interest Disclosures: None.

cryptogenic stroke?21 At what expense would AF prevention prove cost-effective e e alalaltototogegegethththererer fffooor

he reduction of embolic morbidity, if it were achievable? Practically, answering such questions

may y y bebebe ccchahahallllllenee gigiingngng owing to the relatively low eeevveventnn rates and large samamample sizes necessary.

TTTheere efore, at prrreese eennt tt iitit aaappppppeaeaearsrsrs pprrurudededenntn tto exexxeeercise iinccrerereaaasededed vigigigilananancecee foor AAAF F F dededetetetectctctiooonnn innn

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hhhatatat mmmayaay bbbeee ofofof eeembmbmbolololicicic oooriririgigiginnn.


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References:

1. Menke J, Luthje L, Kastrup A, Larsen J. Thromboembolism in atrial fibrillation. Am J Cardiol. 2010;105:502-510.

2. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet. 2009;373:155-166.

3. Lamassa M, Di Carlo A, Pracucci G, Basile AM, Trefoloni G, Vanni P, Spolveri S, Baruffi MC, Landini G, Ghetti A, Wolfe CD, Inzitari D. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke. 2001;32:392-398.

4. Frost L, Engholm G, Johnsen S, Moller H, Henneberg EW, Husted S. Incident thromboembolism in the aorta and the renal, mesenteric, pelvic, and extremity arteries after discharge from the hospital with a diagnosis of atrial fibrillation. Arch Intern Med. 2001;161:272-276.

5. Vohra R, Zahrani H, Lieberman DP. Factors affecting limb salvage and mortality in patients undergoing femoral embolectomy. J R Coll Surg Edinb. 1991;36:213-215.

6. Wasilewska M, Gosk-Bierska I. Thromboembolism associated with atrial fibrillation as a cause of limb and organ ischemia. Adv Clin Exp Med. 2013;22:865-873.

7. Bewelem W CS, Halperin JL, Adabag S, Duval S, Chrolavicius S, Pogue J, Ezekowitz MD, Eikelboom J, Wallentin L, Yusuf W, Hirsch A. Extracranial Systemic Embolic Events in Patients with Nonvalvular Atrial Fibrillation: Incidence, Risk Factors, and Outcomes. Circulation.2015;132:XX-XXX.

8. Investigators A, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, Yusuf S. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066-2078.

9. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.

10. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

11. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial

5. Vohra R, Zahrani H, Lieberman DP. Factors affecting limb salvage and mortalllititity y y ininin pppatatatieieientntntsssundergoing femoral embolectomy. J R Coll Surg Edinb. 1991;36:213-215.

6. Wasilewska M, Gosk-Bierska I. Thromboembolism associated with atrial fibrillation as a causssee e ofofof lllimimimb bb annnddd oroo gan ischemia. Adv Clin Expp MMMedee . 2013;22:865-87333.

777. BBBewelem W CCCSS, HHHaalalpepeperiririnn n JLJLJL, AdAdAdabababagg SSS, DDuuvall SSS, CCChrhrhrolololavavavicciuiuius SS,S PPPogogo ue JJJ,, , EzEzEzekekekowowowitititz MDMDMD,EiEE kekekelboom J, Waaalllentiniin L, YuYuYusuf W, HHHirrschhh AAA. Extxtrrracranananiaiaial SSSystttemmmic EEEmmboooliiic Eveveentntnts iin Patiiienntwiwiwiththth NNNonvaalvlvlvulu aara AAAtriiialll Fibrrrilllalalationonon:: Innnccicideencncnce,e, RRisssk FFFaacactoorrrs,, , anana dd d OuOuutcommesss.k CiCC rculululaaatioon...201555;1;1;1323232:X:X:XX-XXXXXXXX.


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7

fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367:1903-1912.

12. McBane RD, Hodge DO, Wysokinski WE. Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation. Thromb Haemost. 2008;99:951-955.

13. Wysokinski WE, Owen WG, Fass DN, Patrzalek DD, Murphy L, McBane RD, 2nd. Atrial fibrillation and thrombosis: immunohistochemical differences between in situ and embolized thrombi. Thromb Haemost. 2004;2:1637-1644.

14. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012;33:1500-1510.

15. Alonso A, Krijthe BP, Aspelund T, Stepas KA, Pencina MJ, Moser CB, Sinner MF, Sotoodehnia N, Fontes JD, Janssens AC, Kronmal RA, Magnani JW, Witteman JC, Chamberlain AM, Lubitz SA, Schnabel RB, Agarwal SK, McManus DD, Ellinor PT, Larson MG, Burke GL, Launer LJ, Hofman A, Levy D, Gottdiener JS, Kaab S, Couper D, Harris TB, Soliman EZ, Stricker BH, Gudnason V, Heckbert SR, Benjamin EJ. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013;2:e000102.

16. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation.2014;130:2071-2104.

17. Aronsson M, Svennberg E, Rosenqvist M, Engdahl J, Al-Khalili F, Friberg L, Frykman-Kull V, Levin LA. Cost-effectiveness of mass screening for untreated atrial fibrillation using intermittent ECG recording. Europace. 2015;17:1023-1029.

18. Detection of Subclinical Atrial Fibrillation in High Risk Patients Using Implantable Loop Recorder. Accessed July 17, 2015 at https://clinicaltrials.gov/ct2/show/NCT02041832.

19. Prevalence of Sub-Clinical Atrial Fibrillation in Elderly Patients With Hypertension, Detected Using an External Loop Recorder (ASSERT-III). Accessed July 17, 2015 at https://clinicaltrials.gov/ct2/show/NCT02401854.

20. Svennberg E, Engdahl J, Al-Khalili F, Friberg L, Frykman V, Rosenqvist M. Mass Screening for Untreated Atrial Fibrillation: The STROKESTOP Study. Circulation. 2015;131:2176-2184.

21. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J, Investigators CA. Cryptogenic stroke

AM, Lubitz SA, Schnabel RB, Agarwal SK, McManus DD, Ellinor PT, Larson MG,G,, Burke GL, Launer LJ, Hofman A, Levy D, Gottdiener JS, Kaab S, Couper D, Harris TB, Solllimimimananan EEEZ,Z,Z, Stricker BH, Gudnason V, Heckbert SR, Benjamin EJ. Simple risk model predictsss iiincncncididdenenencecece ooof f f atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013;2:e000102.

1666. JaJaJanuary CCCT, Wann LS, Alpert JS, Calkins H, CCCiiigarroa JE, Cllleveveveland JC, Jr., Conti JB, EEElliiinnor PT, Ezekekekowwitititzz z MDMDMD,,, FiFiFieleleldd d MEMEME, MuMurrrrayyy KTT, Saccccccooo RLRLRL, StStStevvvenenensososonn WGGG,, TcTcTchohohou u PJPJPJ, TrTrTracaa yyy CMCMCM, Yancy CWW.. 2201444 AAHAAA/AAACC/HRRRS guidededelinee fffor thhhe e e mmmannnaggemmment off paaatiiients wwwiitith atatrrrial fiibbbrililillall tion: exexexeccutututive suuummmmarara y:y:y: a rererepooorttt of f thththee Ammmeericccaanan CCColllleeeggge oof f f Caaardiooololologygg /AAAmmmericaaan HHHeaartAssoociciciatatatioioion n Taasksksk FFForororcece ooon n pracacactititiccce guiiidededelililinenenesss annndd d thththe HeHeHeararttt RRhR ytytythmhmhm SSSococieieiety. CiCiCircrcrculatttiioionn.202020141414;1;1;1303030:2:2:2070707111-212121040404.


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and underlying atrial fibrillation. N Engl J Med. 2014;370:2478-2486.

22. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH, Jr., Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837-847.


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Table 1. Baseline characteristics, therapeutic comparison, and embolic endpoints in included studies.

ACTIVE-A8

(N=7,554)ACTIVE-W11

(N=6,706)AVERROES9

(N=5,599)RE-LY10

(N=18,113)Therapeutic Comparison Clopidogrel + ASA

vs. ASAClopidogrel + ASA vs.

VKAApixaban vs. ASA† Dabigatran (110mg vs.

150mg)‡ vs. VKA Baseline Characteristics Age 71±10 70±9 70±10 71±9 CHADS2 2.0±1.1 2.0±1.1 2.0±1.1 2.1±1.1 Male gender 58 66 59 64History of Stroke/TIA (%) 13 15 14 20Peripheral arterial disease (%) 3 4 3 -Endpoints Follow-up (median) 3.6 yrs 1.3 yrs 1.1 yrs 2.0 yrs Stroke, all 2.4 vs. 3.3% / yr 2.4 vs. 1.4% / yr 1.6 vs. 3.4% / yr 1.4 vs. 1.0 vs. 1.6% / yr Stroke, ischemic 1.9 vs. 2.8% / yr 2.2 vs. 1.0% / yr 1.1 vs. 3.0% / yr 1.3 vs. 0.9 vs. 1.2% / yr SEE 0.4 vs. 0.4% / yr 0.4 vs. 0.1% / yr 0.1 vs. 0.4% / yr 0.1 vs. 0.1 vs. 0.1% / yr TIA, transient ischemic attack; SEE, systemic embolic event; VKA, vitamin K antagonist; AF, atrial fibrillation; ASA, aspirin; yrs, years. ACTIVE, The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events; AVERROES, Apixiban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy. Continuous measures are reported as mean ± standard deviation. †ASA dose was >81mg in 35% of study patients. ‡ Dabigatran dose was either 110mg or 150mg.

gender 58 66 59 646464ry of Stroke/TIA (%) 13 15 14 202020heral arterial disease (%) 3 4 3 -

points w-up (median) 3.6 yrs 1.3 yrs 1.1 yrs 2.0 yrse, alll 2.4 vs. 3.3% / yr 2.4 vss... 111.4%44 / yr 1.6 vs. 3..4%4%4% / yr 1.4 vs. 1.0 vs. 1.6% e,,, isisischchchemic 1.9 vs. 2.8% / yr 2.2 vs. 1.11 0%00 / yr 1..111 vs. 3.0%0% / yr 1.3 vs. 0.9 vs. 1.2%

0.0.0.444 vsvsv . 0.0.0.4%4%4% /// yyyr 0.0.0.4 4 4 vs. 0.00 %1 / yyyrrr 0.00 1 vsvsvs.. 0.0.0.4%4%4% / yr 00.0.111 vs.. 0.0.0.111 vsvsvs. 000.1%11 rar nsieii nt ischemic attack;; ESEE, s syy teemmmic embmbmbolololic e eeventntnt;;; KKVK ,,A, vit mmamin K a ttntagonoo is ;t;t; AAAF, a rtrtriaalll fibrilii latitt on; SSAS ,,A, asppiririr nnin; yrs, yyyeaee rsrsrs. CCACTIIIVEVV , ThTT e e e Ataaati nnon Clopidogrel Trial wwwith h Irbesass ttrtan for P eerevention of VVVa ccscular EEE eevents; AAA EEVERROEOEES,S,S, AAApipp xixx ban versrr us A eecetylsll al cicicylici Acid tott PPPre eveent Strokkee nnin Aatitition PPatients Whoo hahh ve Faia led roror AAAre U ssnsuiu atatable for ViVV tamimm n nn K nnAn atagog ni ttst Trerr atmemm ntntn ; EERE LL-LY, Ranaa dodd mized dd vvEval aauationonon of Lonnn --g-Te mrmm AAAntic aoa uugulatpy. CCC nnontititinunuous s mememeasaa ur sses a eere repporoo eeted d as meaeaean ±±± stststananandadadard dddeviaiaiatititiononon.. AA†ASASS dddose ee aawas >8>8>81m1mmg gg nnin 333 %5%5% off f stststuduu y y papp titit ents. ‡‡‡ DaDaD bigagagatrararan dosess wwwas e titit eeher r 1ttmg.


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Figure Legend:

Figure 1. Schematic representation of risk assessment in atrial fibrillation (AF). Pre-diagnosis,

the role of enhanced surveillance may be considered for patients at increased risk of AF, stroke,

and systemic embolic events (SEEs). The CHARGE-AF score (inclusive of age, race, height,

weight, blood pressure, smoking status, use of anti-hypertensive medication, diabetes, history of

myocardial infarction and heart failure) has demonstrated discrimination in the prediction of

AF.15 Post-diagnosis, risk assessment and implementation of thromboembolism prophylaxis is

often guided by the CHA2DS2-VASc algorithm.16 The circles display the relatively increased

incidence of stroke as compared to SEE. Enclosed in the circles are risk factors that may

selectively predispose to either stroke or SEE. AF, atrial fibrillation; CHARGE-AF, Cohorts for

Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation; SEE, systemic embolic

event; LA, left atrial; LAA, left atrial appendage.

ncidence of stroke as compared to SEE. Enclosed in the circles are risk factors thahahat t t mamamayy y

electively predispose to either stroke or SEE. AF, atrial fibrillation; CHARGE-AF, Cohorts for

Heararrttt ananand d d AgAgAging g g ReRR search in Genomic Epidemioioolllogogogy Atrial Fibrillationnn; SEE, systemic embolic

evevevenenent; LA, lefft atatatriiall;;; LALALAA,A,A, lllefefefttt atatatriririalalal aaapppennndadadage.


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Neal A. Chatterjee and Steven A. LubitzSystemic Embolic Events (SEE) in Atrial Fibrillation: SEEing Embolic Risk More Clearly

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2015 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online July 29, 2015;Circulation.

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